Indole Alkaloids

The tetrahydro-β-carboline moiety is a sub-structure common to hundreds of indole alkaloids natural products, including the intricate cage-like (+)-ajmaline, an anti-arrhythmic agent obtained from the roots of Rauwolfia serpentine, an evergreen shrub found in tropical regions.

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images © dinesh valke and used with permission

 A major synthetic problem has been accessing the cis-1,3-disubstituted derivatives required for (+)-ajmaline and related natural products, such as (−)-raumacline and (−)-suaveoline.

alkaloids

By a careful study of the mechanism of the Pictet-Spengler reaction, we developed the first general (and asymmetric) route to cis-1,3-disubstituted tetrahydro-β-carbolines, starting from L-tryptophan.1,2 We have found that some reagent pairings give exceptional cis-selectivity in this kinetically controlled Pictet-Spengler reaction (Scheme 1) and we have applied this to the synthesis of several natural products and analogues, including the total synthesis of (−)-suaveoline.3

Pictet Spangler
Scheme 1 - cis-selective Pictet Spengler reaction

We have developed a synthetic route to the ajmaline family of indole alkaloids which selectively introduces four of the chiral centres required for both (−)-raumacline and (+)-ajmaline through the use of a cis-selective Pictet Spengler reaction (Scheme 1), which installs the stereochemistry at C3 and a Michael reaction/lactonisation sequence (Scheme 2) which selectively installs the key stereochemistry at C15 and C16.

michael reaction  
Scheme 2 - Michael reaction / lactonisation sequence

We have applied this methodology in our total synthesis of (−)-raumacline4 and are also using it in ongoing work towards (+)-ajmaline.

References

  1. P. D. Bailey, S. P. Hollinshead, N. R. McLay, K. M. Morgan, S. J. Palmer, S. N. Prince, C. D. Reynolds and S. D. Wood, J. Chem. Soc. Perkin Trans. 1, 1993, 431-439. DOI
  2. L. Alberch, P. D. Bailey, P. D. Clingan, T. J. Mills, R. A. Price and R. G. Pritchard, Eur. J. Org. Chem., 2004, 1887. DOI
  3. P. D. Bailey, and K. M. Morgan, J. Chem. Soc., Perkin Trans. 1, 2000, 3578. DOI
  4. P. D. Bailey, P. D. Clingan, T. J. Mills, R. A. Price and R. G. Pritchard, Chem. Commun., 2003, 2800. DOI